This invention relates to the detection and treatment of hereditary disease, and in particular to the detection and diagnosis of Duchenne, Becker and Outlier muscular dystrophies (MD) by various methods.
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder which affects about 1 in 3,300 males. Traits associated with DMD (DMD phenotype) are well known and may include elevated creatine phosphokinase levels in serum (at least 10.times. the normal level), delayed development of motor function, and muscle weakness characterized by the replacement of muscle fiber with adipose and fibrose tissue accompanied by a marked variation in muscle size. Until recently, carrier identification in DMD families generally was accomplished by detecting elevated levels of creatine phosphokinase in serum.
Becker muscular dystrophy (BMD) is also an X-linked recessive genetic disorder, but occurs at only 10% of the frequency of DMD. BMD is a more benign form of muscular dystrophy which follows a less rapid clinical course than DMD. Both DMD and BMD are caused by mutations in the DMD gene located in the Xp21 region of the short arm of the human X chromosome.
Outlier muscular dystrophy (OMD) is a mild Duchenne/severe Becker disorder. It forms a subgroup that comprises approximately 10 percent of individuals inflicted with DMD.
Restriction fragment length polymorphisms (RFLPs) occur when the genomic DNA sequence in a population of animals varies such that complete digestion with a restriction endonuclease will result in a set of restriction fragments of one or more different size arrays. The differences are due to the presence or absence in the DNA sequence of sites recognized by the endonuclease; a sequence in which the site is present will be cut by the endonuclease giving one array, and a sequence in which the site is not present will fail to be cut by the endonuclease, giving another array.
It has been shown that RFLPs which are located near a gene associated with a hereditary disease can be used to determine the likelihood of a particular person having a defective gene and thus having the disease. Bakker et al., The Lancet, Mar. 23, 1985, at 655 describes "eleven RFLP-markers . . . on the short arm of the X chromosome [that] are useful in the diagnosis of DMD since they bridge the Duchenne locus at genetic distances varying between 3 and 20 centiMorgans."